Among the congenital cardiomyopathies, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC) are the most prevalent forms. These cardiomyopathies cause either dilated (systolic) or restrictive (diastolic) physiology, life-threatening arrhythmias, and increased risk or thromboembolism. It is well known that many genetic causes are overlapping among DCM, HCM and LVNC; however, the prediction of specific phenotype is not yet possible because of lack of understanding on their molecular mechanisms. To overcome the problem, in this R01 grant, we will generate human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with inherited DCM, HCM and LVNC as well as matched family controls and healthy unrelated controls. In order to clarify the detailed genotype-phenotype correlations, we will elucidate structural, electrophysiological, developmental, transcriptome, and mechanistic analyses using these patient-specific lines as well as genome-edited isogenic iPSC lines. Importantly, we will also perform studies among groups that manifest (a) same disease phenotype but different mutation genes, and (b) different disease phenotype which have different mutant alleles in the same genes. Collectively, these studies will uncover not only phenotype- specific underlying pathogenesis but also the mutation-specific pathogenesis in common genetic causes of congenital cardiomyopathies.